1-(5-nitro-2-furyl)-2-(beta-pyridyl)-ethylene and process for preparation thereof



United States Patent 1-(S-NITRO-2-FURYL)-2-(}3-PYRIDYL)-ETHYLENE AND PROCESS FOR PREPARATION THEREOF Shinsaku Minami, Yamatokoriyama-shi, Akio Fujita,

Ibaragi-shi, Tadatsugu Yamamoto, Osaka, Katsuro Fujimoto, Neyagawa-shi, Osaka-fu, Masanao Shimizu,

Kobe-shi, and Yoshiyuki Takase, Amagasaki-shi, Japan,

assignors to Dainippon Pharmaceutical Co., Ltd., Higashi-ku, Osaka, Japan, a corporation of Japan N0 Drawing. Filed Feb. 4, 1965, Ser. No. 430,490

2 Claims. (Cl. 260-240) The present invention relates to the new nitrofuran compound 1 (5-nitro-2-furyl)-2-(p-pyridyD-ethylene represented by the formula:

It is known that 1-(5-nitro-2-furyl)-2-(u-(or 'y-)-pyridyl)-ethylene can be prepared by condensing S-nitrofurfural with a-(or -)-methylpyridine and that the compound exhibits antibacterial activity (Belgian Patent No. 613,604 and Belgian Patent No. 615,319).

However, these compounds are found to be active in vitro tests, but not in vivo tests.

It is one object of the present invention to produce a nitrofuran compound which has anti-bacterial, fungal and protozoal activities both in vitro and in vivo.

Another object of the present invention is to provide a process of making such a new and valuable nitrofuran compound.

Still another object of the present invention is to pr0- vide pharmaceutical compositions useful in therapy which contain such a new 5-nitrofuran compound as active ingredient.

Other objects of present invention and advantageous features thereof will become apparent as the description proceeds.

The nitrofuran compound according to the present invention completely inhibits the growths of bacteria, fungi and protozoa, such as Escherichia coli, Shigella jlexneri, Staphylococcus aureus, Mycobacterium tuberculosis, Candida albicans, Trichophyton asteroides and T richomonas vaginalis in vitro tests.

Further,'the following tables show that 1-(5-nitro-2- furyl)-2-(B-pyridyl)-ethylene [I] possesses remarkably high in vivo activities against Salmonella typhimurium and Candida albicans infected male mice. The compound was compared with both 1-(5-nitro-2-furyl)-2-(a-pyridyl)-ethylene [II] and 1-(5-nitro-2-furyl)-2-(y-pyridyl)- ethylene [III].

TABLE 1.EFFEC'IS ON THE INFECTION WITH SALMONELLA TYPHIMURIUM Drug Dose 1 (mg/kg.) (1) (II) (III i.p. p.o. i.p. p.o l.p. p.o

tlv y.

2 Survival numbers of mice/total used numbers of mice.

TABLE 2.EFFECTS ON THE INFECTION WITH BOTH CANDIDA ALBI CANS Drug Dose 1 (mg/kg.)

1 Drugs were given by the lntraperltoneal and oral routes five times 0, 5, 10, 24 and 30 hours after intravenous infection, respectively.

2 Survival numbers of mice/total used numbers of mice.

The l (5 nitro 2 furyl) 2- (,3 pyridyl) ethyllene has proved to be of considerable value in the prophylaxis or the treatment of systemic infections with microorganisms by oral administration. It may be also used for the treatment of the infections by topical application.

The 1-(5-nitro-2-furyl)-2-( 3-pyridyl)-ethylene can not be prepared by condensing S-nitrofurfural with st-methyl pyridine, since the fi-methyl group is not reactive.

The present invention provides a process of making 1 (5 nitro 2 furyl) 2 (,B pyridyl) ethylene which comprises condensing S-nitrofurfural with an alkali salt of (fi-pyridyl) acetic acid in the presence of aceticanhydride to form l-(5-nitro-2-furyl)-2-hydroxycarbonyl- Z-(B-pyridyD-ethylene, followed by the decarboxylation of said 1-(5-nitro-2-furyl)-2-hydroxycarbonyl-2-(pi-pyridyl)-ethylene intermediate in the presence of copper chromite.

The condensation between S-nitrofurfural and (p-pyridyl)-acetic acid can be easily effected in the presence of acetic anhydride at room temperature, since the methylene group of (fl-pyridyD-acetic acid is reactive. In this reaction an elevated temperature is unfavorable owing to the decomposition of the product.

The 1-(5-nitro-2-furyl)-2-(;8-pyridyl)-ethylene can be prepared effectively by decarboxylation with heating of 1- (5 nitro 2 furyl) 2 hydroxycarbonyl 2 (B pyridyl)-ethylene in the presence of copper chromite as a catalyst in a suitable solvent, such as quinoline or aniline.

The following examples illustrate an effective process for producing the new compound.

Example I To a solution of 10.5 g. of S-nitrofurfural in 149 g. of acetic anhydride was added 13.0 g. of potassium S-pyridyl)-acetate, and the mixture was stirred for 4 hours at room temperature (20-30 C.). Yellow crystals which separate out were dissolved in 10% aqueous potassium carbonate. The solution was acidified with glacial acetic acid and crystals which separate out were filtered, Washed with water and dried to give 15.3 g. of 1-(5-nitro-2-furyl)- 2-hydroxycarbonyl-2-(fi-pyridyD-ethylene, M.P. 240-242" C. (dec.).

Example 2 A mixture of 25 g. of quinoline and 0.3 g. of copper chromite was heated at 180 C. To the mixture, 30 g. of 1 (5 nitro 2 furyl) 2 hydroxycarbonyl 2 (B pyridyl)-ethylene was added in portions with stirring during 30 minutes. After cooling, the quinoline was evaporated under reduced pressure. The residue was washed with ether and recrystallized from isopropanol to give 1.2 g. of 1-(5-nitro-2-furyl)-2-(fl-pyridyl)-ethylene, M.P. 121 C.

3 What is claimed is: 1. The compound 1-(S-nitro-Z-furyl)-2-(p-pyridyl)- ethylene represented by the formula:

4 decarboxylation of said 1-(5-nitro-2-furyl)-2-hydroxycarbonyl-2-(fl-pyridyl)ethylene intermediate in the presence of copper chromite.

References Cited FOREIGN PATENTS 5/1963 Great Britain.

OTHER REFERENCES Klingsberg: Pyridine and Derivatives, part 2, page 200, Interscience Pub., N.Y. (1961).

JOHN D. RANDOLPH, Primary Examiner. 

1. THE COMPOUND 1-(5-NITRO-2-FURYL)-2(B-PYRIDYL)ETHYLENE REPRESENTED BY THE FORMULA:
 2. THE PROCESS FOR PREPARING (-(5-NITRO-2-FURYL)-2(BPYRIDYL)-ETHYLENE WHICH COMPRISES CONDENSING AN ALKALI SALT OF (B-PYRIDYL)-ACETIC ACID WITH 5-NITROFURFURNAL IN THE PRESENCE OF ACETIC ANHYDRODE TO FORM 1-(5-NITRO-2-FURYL)2-HYDROXYCARBONYL-2-NB-PYRIDYL)-ETHYLENE, FOLLOWED BY DECARBOXYLATION OF SAID 1-(5-NITRO-2-FURYL)-2-HYDROXYCARBONYL-2-(B-PYRIDYL)-ETHYLENE INTERMEDIATE IN THE PRESENCE OF COPPER CHROMITE. 